There is evidence that the complement (C), a major mediator of inflammatory responses may play an important role in Alzheimer's disease (AD) neuropathology. The proposed studies focus on brain experimental lesions to model select aspects of AD and aim at the understanding the role of C in mechanisms of hippocampal neuron death/survival and synaptic plasticity. In preliminary studies, we found that subsets of hippocampal pyramidal neurons in congenic mice genetically deficient of C component C5 (C5-) are more susceptible to glutamate neurotoxicity when compared to C5 sufficient (C5+) mice. We also found that the C5 derived anaphylatoxin C5a, diminished glutamate mediated neurotoxicity in hippocampal neuron cultures. We will attempt to further dissect the mechanisms which may underlie the neuroprotective role of the pro.inflammatory anaphylatoxin C5a. Specifically, we will attempt: (l.) characterize the role of C5a in hippocampal responses to experimental lesions using a C5a-receptor (C5aR) knockout mouse model, (2.) identify the actions of C5a on hippocampal neurons in intact adult brain and with experimental lesions, (3.) characterize the trophic /neuroprotective actions of hrC5a on hippocampal neuron in culture, (4.) characterize in C5-, C5+ and C5aR knockout mice altered glutamate receptors gene expression which we hypothesize might be under C5a control. These studies will clarify the role of C in brain and will lead to better understanding the mechanisms which may underlie the neuroprotective role of the anaphylatoxin C5a. They may lead to a better understanding of C mediated pathophysiology in AD.